Several new drug conjugates of monoclonal antibodies and or response modifiers have been synthesized. A major focus has been on the development of reproducible, simple, and efficacious methods for synthesis of these conjugates. Drug conjugates of 9.2.27, a monoclonal antibody to the 250K proteoglycan of human melanoma, and to a lesser extent D3, a monoclonal antibody to the guinea pig line 10 hepatoma, have been made. The drugs utilized include actinomycin-D, (ACT-D), 5-Fu, Daunomycin, Ara-C, and methotrexate. We are now concentrating on ACT-D conjugates of 9.2.27 to determine optimal yield, specificity, activity in vitro, and in vivo, as well as in vivo tumor localization. Preliminary in vitro cytotoxicty studies have been carried out with conjugates of all the aforementioned drugs using antigen positive melanoma cells (FeMx), and antigen negative melanoma cells (A375). The ACT-D conjugates of 9.2.27 appear to have immunologic specificity as well as potency. Further efforts are now being made to determine optimal conjugation ratios, using poly-L-lysine of various sizes as initial carriers of drugs to be conjugated to monoclonal antibodies. Further studies are being carried out to optimize in vitro delivery to tumor sites and minimize non-specific uptake especially in the reticuloendothelial system (RES) by using the following approaches; the use of monoclonal antibodies with covalently modified polyethyleneglycol monomethyl ether (PEG); pretreatment of animals with heat aggregated human gamma globulin; and the use of monoclonal immunoglobulins of the same subtype.